ACCESSION NO: 96-97-0774
TITLE: A Role at Last for Mad Cow Protein
AUTHOR: COHEN, PHILIP
JOURNAL: New Scientist
CITATION: April 20, 1996, 150(2026): 18.
YEAR: 1996
PUB TYPE: Article
IDENTIFIERS: PRION DISEASES; PROTEIN PRP; BRAIN CELLS; PURKINJE CELLS;
BALANCE; MUSCLE FUNCTION; MUTANT MICE; FATAL FAMILIAL
INSOMNIA; CREUTZFELD-JAKOB DISEASE (CJD); MAD COW DISEASE;
BOVINE SPONGIFORM ENCEPHALOPATHY (BSE)
ABSTRACT: Mad cow and other spongiform encephalopathies or prion
diseases are thought to be caused by an altered form of a
protein, called PrP, which is normally found on the outside
of nerve cells in the brain. No purpose had been identified
for the protein, but now scientists have found that it
prevents certain brain cells from dying prematurely and helps
control rhythms of sleep and wakefulness.
Prion diseases occur when an insoluble form of PrP with
an unusual shape, takes over part of the brain. The altered
PrP can arise spontaneously by genetic mutation or can enter
the body from outside. Once a small amount of PrP is present
it can convert normal PrP to the dangerous form.
Scientists were unable to demonstrate any ill effects in
mice with crippled versions of the gene for PrP. The lack of
PrP actually appeared beneficial, because the mice became
completely resistant to prion diseases. This led to hopes
that a drug which could knock out PrP might help cure or
prevent Creutzfeld-Jakob Disease, the most common human prion
disease. Unfortunately, these hopes were premature. When
researchers removed the whole gene for PrP (previous
researchers had produced mice lacking only a large part of
it), the mice developed wobbly legs and could not walk
straight. When researchers examined the brains of the mice
they found that they lacked up to 95% of the Purkinje cells
of the cerebellum which are essential for balance and muscle
function.
The part that PrP plays in keeping the Purkinje cells
alive was probably not apparent in the earlier study because
the crippled form of the protein can fulfill this role.
Researchers believe that some of the symptoms of prion
diseases may be caused by the loss of Purkinje cells as well
as by the toxic effects of the insoluble form of the protein.
A team of Swiss researchers has now investigated the PrP
mutant mice used in the earlier experiment and have found
that they have abnormal sleep patterns. The mice wake up
repeatedly for periods of up to 16 sec. This may explain why
sleep disruption is one of the first symptoms reported by
patients with fatal familial insomnia, an extremely rare
inherited human prion disease.
ACCESSION NO: 96-97-0754
TITLE: BSE Transmission to Macaques
AUTHOR: LASMEZAS, C. I.; DESLYS, J. P.; DEMAIMAY, R.; ADJOU, K. T.;
LAMOURY ET AL., F.
JOURNAL: Nature
CITATION: June 27, 1996, 381(6585): 743-744.
YEAR: 1996
PUB TYPE: Article
IDENTIFIERS: CREUTZFELDT-JAKOB DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY
(BSE); CYNOMOLGUS MACAQUES; CATTLE BRAIN EXTRACTS; PRION
PROTEIN ACCUMULATION; CEREBELLAR DAMAGE; DISEASE
TRANSMISSION; ANIMAL-HUMAN TRANSMISSION
ABSTRACT: A new variant of Creutzfeldt-Jakob Disease (CJD) with a
unique clinicopathological presentation may be linked to the
disease bovine spongiform encephalopathy (BSE) in British
cattle. Similar clinical, molecular, and neuropathological
features have been observed in three BSE-infected macaque
monkeys and 12 human cases of vCJD. In the human cases,
spongiosis was evident in the striatum and thalamus, and was
present in cortical areas and in the cerebellum. Abundant
florid plaques, large cortical deposits of pathological prion
protein, were present in both the macaques and the humans.
The study provides evidence that the BSE agent in macaques is
identical to that of vCJD in humans.
Two adult cynomolgus macaques and a neonate were
inoculated intracerebrally with brain extracts of British
cattle suffering from BSE. The two adults developed abnormal
behavioral signs such as depression, edginess, and a
voracious appetite after 150 wk. Both developed cerebellar
signs with truncal ataxia, broad-based gait and tremors, and
priapism. Behavioral changes worsened as the disease
progressed, and after 10 wk. and 11 wk. of disease, the adult
macaques were killed. The youngest macaque showed similar
clinical signs 128 wk. after inoculation and was killed at
the same clinical stage as the adults.
The amounts of abnormal prion protein accumulation in
different brain regions of the three animals were similar to
that described in vCJD. Spongiform change and astrogliosis
were intense in the thalamus and the striatum and severe in
the granular and molecular layers of the cerebellum and the
cerebral cortex. Numerous plaques consisted of a central
eosinophilic dense core surrounded by a pale periphery. Such
lesions were identical to florid plaques described in vCJD.
The regional distribution of different types of prion protein
deposits was similar in the monkey and the humans.
Cynomolgus macaques belong to Old World monkeys and
represent the evolutionary nearest experimental model to
humans. Though the macaques were inoculated intracerebrally
and human contamination with BSE was through an oral route,
researchers have shown that the pathology at the terminal
stage of disease does not depend on the inoculation route.
The study results show that the BSE agent is responsible for
the emergence of the new form of CJD in humans.
ACCESSION NO: 96-97-0466
TITLE: Who Gets Creutzfeldt-Jakob Disease?
AUTHOR: RIDLEY, R. M.; BAKER, H. F.
JOURNAL: British Medical Journal
CITATION: November 25, 1995, 311(7017): 1419.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: CREUTZFELDT-JAKOB DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY
(BSE); KURU; INCUBATION PERIODS; CROSS SPECIES TRANSMISSION;
GREAT BRITAIN; SPECIFIED OFFALS BAN OF 1989; MAD COW DISEASE;
PRION DISEASES
ABSTRACT: Whenever an unusual case of Creutzfeldt-Jakob disease is
reported in Britain someone asks: "Is this the beginning of
the end--are we all going to die of bovine spongiform
encephalopathy?" It is a commonly held view that the
incubation period for spongiform encephalopathy in humans is
at least two decades. This is a misconception. For kuru, when
the dose of infectivity by the oral route was high, the
minimum incubation period was less than 4 yr. and the median
ranged from less than 5 yr. to 9 yr. (judged by the minimum
age of onset at the height of the epidemic). However, the
incubation period can be as long as 30 yr. (judged by the
ages of the most recent cases).
While experimental transmission of spongiform
encephalopathy across species generally results in increased
incubation times, this is because the "species barrier"
increases the dose required, so that few individuals are
affected. It is now 6-9 yr. since the general public was at
great risk of consuming meat products containing brain tissue
from cattle incubating bovine spongiform encephalopathy (BSE)
(that is, between the emergence of this disease in 1986 and
the Specified Offals Ban of 1989), so it is already clear
that a substantial proportion of the population will not be
affected. Nonetheless, the occurrence of only a handful of
cases of human spongiform encephalopathy resulting from
exposure to BSE would be a tragedy, and any possible case
warrants close examination. It is, however, another
misconception to suppose that every case of Creutzfeldt-Jakob
disease must have been caught from somewhere. About 15% of
cases are wholly genetic in origin, and in nearly all the
remaining cases persistent and extensive epidemiological
investigation has failed to find a contamination event,
leading to the proposition that these cases are idiopathic.
ACCESSION NO: 96-97-0465
TITLE: Epidemiological Evidence Concerning a Possible Causal Link
AUTHOR: HOFMAN, ALBERT; WIENTJENS, DOROTHeE P. W. M.
JOURNAL: British Medical Journal
CITATION: November 25, 1995, 311(7017): 1418-1419.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: CREUTZFELDT-JAKOB DISEASE; DAIRY FARMERS; BOVINE SPONGIFORM
ENCEPHALOPATHY (BSE); CROSS SPECIES TRANSMISSION; EUROPEAN
SURVEILLANCE STUDY; MAD COW DISEASE; PRION DISEASES
ABSTRACT: The occurrence of Creutzfeldt-Jakob disease in British
dairy farmers possibly exposed to cattle with bovine
spongiform encephalopathy (BSE) has also focused attention on
the possibility of a causal link between the two diseases.
Epidemiological evidence concerning occupational
exposure has been derived from two sources: a meta-analysis
of three case-control studies, conducted in Japan, Britain,
and the U.S., and an ongoing European case-control study
based on the registries of Creutzfeldt-Jakob disease that
were started in 1992. The meta-analysis included data on 178
cases of Creutzfeldt-Jakob disease and 333 controls. In 95
cases information on occupational exposure to cattle was
available, and 26 subjects had been exposed. The
corresponding figures for the controls were 26 out of 145.
The resulting relative risk for exposure was 1.7.
A preliminary analysis from the ongoing European case-
control study included 234 cases of people with the disease,
of whom 24 had ever been occupationally exposed to cows, and
237 controls, of whom 19 had ever been exposed. The relative
risk amounted to 1.3.
Although the occurrence of Creutzfeldt-Jakob disease in
four dairy farmers in Britain is clearly a matter of concern,
the current evidence from the European surveillance study
suggests that there is no higher risk of the disease in
British dairy farmers than in farmers in other European
countries. Furthermore, the overall incidence of Creutzfeldt-
Jakob disease is similar in the five European countries,
while there is a substantial difference in the incidence of
BSE. Taken together, the epidemiological evidence to date
does not point to a causal link between BSE and Creutzfeldt-
Jakob disease but, unfortunately, does not strongly reject
that possibility either.
ACCESSION NO: 96-97-0464
TITLE: The Jury Is Still Out
AUTHOR: BROWN, PAUL
JOURNAL: British Medial Journal
CITATION: November 25, 1995, 311(7017): 1416.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: CREUTZFELDT-JAKOB DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY
(BSE); CATTLE PRODUCTS; INHALANT INFECTION; CROSS SPECIES
TRANSMISSION; FARMERS; HEALTH RISKS; MAD COW DISEASE; GREAT
BRITAIN; PRION DISEASES
ABSTRACT: Creutzfeldt-Jakob disease has now been identified in
four farmers and two adolescents in Britain, where its bovine
spongiform counterpart has been epidemic for the past several
years. Is there a connection? This question is being
discussed by many different groups according to preexisting
biases and professional goals, as might be expected for so
controversial and potentially explosive a topic. The media
has in the main sounded alarm bells because its goals is to
prevent unwarranted panic; and medical science has been
somewhat unpredictably divided in its evaluation, depending
at least in part on individuals' distaste or flair for
publicity.
In fact, no one can yet say with any confidence whether
these cases of Creutzfeldt-Jakob disease in adolescents and
farmers are the result of infection with bovine spongiform
encephalopathy (BSE). In favor of the idea is the fact that
so-called sporadic Creutzfeldt-Jakob disease is typically a
disease of late middle age, with only a handful of cases in
people aged under 25; the disease would, however, be expected
to occur in a more uniform age distribution if the source of
infection was ingestion of cattle products, which explains
the concern about "back-to-back" cases in young people. With
respect to the four farmers, it is also true that each had at
least one infected cow in his herd, raising the possibility
of contact infection from the cows or even inhalant infection
form the contaminated meat and bone meal feed that caused
their illness.
Against the idea is the fact that adolescent Creutzfeldt-
Jakob disease has occurred at times and places that virtually
exclude the possibility of infection with BSE and that
farmers have died of Creutzfeldt-Jakob disease in countries
where BSE does not occur.
ACCESSION NO: 96-97-0463
TITLE: More than Happenstance: Creutzfeldt-Jakob Disease in Farmers
and Young Adults
AUTHOR: GORE, SHEILA M.
JOURNAL: British Medical Journal
CITATION: November 25, 1995, 311(7017): 1416-1419.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: CREUTZFELDT-JAKOB DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY
(BSE); CROSS SPECIES TRANSMISSION; CATTLE PRODUCTS; FARMERS;
HEALTH RISKS; SHEEP; SCRAPIE; MAD COW DISEASE; DISEASE
TRANSMISSION; GREAT BRITAIN; PRION DISEASES
ABSTRACT: In 1986, four years after a change in the processing of
offals--including those from sheep infected with scrapie--
into cattle meal, the first British case of bovine spongiform
encephalopathy (BSE) was confirmed. Median incubation period
in cattle is around 4-5 yr. By April 14, 1995, BSE had been
confirmed in 53.3% of dairy herds, 14.7% of beef suckler
herds, and 33.8% of all herds with adult breeding cattle;
people who work on farms without confirmed cases of BSE may,
however, have worked on farms with infected, but not
affected, cattle. The air of ongoing studies in cattle is to
find evidence of direct transmission of BSE by the two
suggested means of transmission of scrapie in sheep: from
mother to offspring or between related animals around
parturition.
The incubation period of human spongiform
encephalopathies--kuru and Creutzfeldt-Jakob disease--is
poorly estimated from data but is apparently in the range of
15-40 yr., possible shorter in people who were young at
exposure. The potential for the agent responsible for BSE to
cross species barriers after occupational or dietary exposure-
-including exposure to cattle meal by ingestion or inhalation-
-has been a major concern for human health. Whether the agent
is pathogenic to humans cannot be known by direct
experimentation. Thus, surveillance of cases of sporadic
Creutzfeldt-Jakob disease--in terms of occupational
distribution, temporal changes in incidence, and dietary
correlations--is the only way to get early warning of
pathogenesis of BSE in humans.
Cases of Creutzfeldt-Jakob disease in farmers and young
adults are more than happenstance. They signal an
epidemiological alert to investigate intensively possible
exposures--farm-related and dietary--and to devise means of
doing so that are minimally compromised by preexisting
publicity.
ACCESSION NO: 96-97-0462
TITLE: Will Bovine Spongiform Encephalopathy Transmit to Humans?
AUTHOR: ALMOND, JEFFREY W.
JOURNAL: British Medical Journal
CITATION: November 25, 1995, 311(7017): 1415-1416.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: BOVINE SPONGIFORM ENCEPHALOPATHY (BSE); CREUTZFELDT-JAKOB
DISEASE; CROSS SPECIES TRANSMISSION; CATTLE; GREAT BRITAIN;
FARMERS; HEALTH RISKS; PRION DISEASES; MAD COW DISEASE
ABSTRACT: Two cases of sporadic Creutzfeldt-Jakob disease have
recently been reported in teenagers in Britain, adding to
only four cases previously reported in this age group. Four
British dairy farmers have died from the same disease in the
past 3 yr.--an occupational association that is unlikely to
have arisen by chance. Researchers are questioning whether
the agent responsible for Creutzfeldt-Jakob disease could be
transmitted to humans from cattle affected with bovine
spongiform encephalopathy (BSE).
The possibility that BSE might transmit to humans has
been acknowledged since the disease was first recognized in
British cattle. Indeed, one of the control measures
introduced in 1989--that of removing certain offals from
bovine carcasses--was designed to minimize the risk of
transmission to humans.
Any change in the pattern of presentation of Creutzfeldt-
Jakob disease in Britain compared with countries free of BSE
would be cause for concern. However, the incidence of
Creutzfeldt-Jakob disease in Britain has shown no significant
increase in recent years and is similar to that elsewhere.
The cases in farmers do suggest a significantly elevated risk
for this group versus the general population. However, an
elevated risk is also observed for farmers in other countries
where there is zero or very low incidence of BSE. The risk is
therefore unlikely to be related to BSE. The cases in
teenagers are possible of greater concern since such cases
are generally extremely rare. However, it is possible that in
earlier times, when there was less awareness of the disease,
cases in teenagers were misdiagnosed. Researchers need be
sure that the present cases are more than simply coincidental
before they conclude that they represent a real change in the
presentation of Creutzfeldt-Jakob disease.
ACCESSION NO: 96-97-0234
TITLE: Ten Deaths that May Tell a Shocking Tale
AUTHOR: PAIN, STEPHANIE
JOURNAL: New Scientist
CITATION: March 30, 1996(2023)
YEAR: 1996
PUB TYPE: Article
IDENTIFIERS: PRIONS; BOVINE SPONGIFORM ENCEPHALOPATHY (BSE); CREUTZFELDT-
JAKOB DISEASE (CJD); MAD COW DISEASE; ENGLAND; BEEF; COWS;
HEALTH
ABSTRACT: Because of the recent outbreak of bovine spongiform
encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD),
research on prions has increased. Prions are lethal proteins
that have been traced and determined to cause these diseases.
Researchers hope that by studying the structure of these
proteins they will be able to understand how they cause these
devastating diseases.
In the early 1980s, manufacturers of high-protein animal
feed obtained prions by grinding up and turning sheep
carcasses and mixing them with other ingredients. This
mixture was then fed to cattle. However, some of the sheep
suffered from a prion-related disease called scrapie which
led to the current BSE epidemic that has killed 158,000
British cattle. In addition to that, BSE is being blamed for
causing CJD in humans and recently killing 10 young people
who probably acquired the disease after consuming beef in the
mid-to-late 1980s.
CJD has an incubation period of decades. It affects one
in a million people each year but because its incubation
period is so long it is mostly the elderly who show signs of
it. The 10 young victims ranged from 18-41 yr. with an
average age of 27 yr. Where as in elderly sufferers the
symptoms ranged from forgetfulness to odd behavior, in young
victims it shows up in the form of depression and anxiety.
CJD usually takes an average of 6 mo. to kill but the recent
10 new cases have taken an average of 13 mo.
Because of this inconsistency, scientists are
speculating that these incidents might be the first human
cases of BSE. More studies need to be done on the brain
tissue of the victims to determine if it is a strain of BSE.
Results are expected to take up to 9 mo. Since no one knows
how many people have been exposed to contaminated beef, nor
how big a dose is needed to cause the disease, British
officials are reluctant to speculate. If it is BSE in origin
the numbers should rise rapidly in the next 6-12 mo.
ACCESSION NO: 95-96-2253
TITLE: Unaltered Susceptibility to BSE in Transgenic Mice Expressing
Human Prion Protein
AUTHOR: COLLINGE, JOHN; PALMER, MARK S.; SIDLE, KATIE C. J.
JOURNAL: Nature
CITATION: December 21//28, 1995, 378(6559): 779-783.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: PRION DISEASES; NEURODEGENERATIVE DISEASES; BOVINE SPONGIFORM
ENCEPHALITIS (BSE); SCRAPIE; CREUTZFELD-JAKOB DISEASE (CJD);
PRION PROTEIN (PRP); SPECIES BARRIERS; DISEASE TRANSMISSION
ABSTRACT: Prion diseases, such as bovine spongiform encephalitis,
scrapie of sheep, and Creutzfeld-Jakob disease of humans, are
transmissible neurodegenerative diseases. Prions consist
mainly of a post-translationally modified form of prion
protein (PrP), PrPSc, which is partly protease resistant.
Prion proteins are found in the brain and result in disease
when they are converted to the protease-resistant form.
Interspecies transmission of prions is limited by a "species
barrier," determined partly by the degree of sequence
homology between host PrP and inoculated PrPSc and the strain
of prion.
The epidemics of bovine spongiform encephalitis (BSE) in
the U.K. and in other countries has led to public fear that
human infection could occur from eating beef from infected
animals. BSE appears to be caused by a single strain of
prion, distinct from the strains which cause natural or
experimental scrapie, which is seen also in the new prion
diseases in cats and ruminants believed to be caused by
ingestion of BSE-contaminated food. Experiments with
transgenic mice were conducted to see if BSE could cross the
species barrier and result in CJD in people who have eaten
infected beef. The low incidence and long incubation periods
of these diseases--possibly decades--mean that it would be
years before surveillance studies show if this is occurring.
Transgenic mice expressing human and mouse PrP were
challenged with CJD or BSE inocula, to see if they could
produce human PrPSc and "human" prions. The mice were also
challenged with inocula of several other prion diseases,
including two inherited disorders that were not transmissible
to primates (fatal familial insomnia and an unnamed disease).
Wild type mice have been shown to be susceptible to BSE. In
transgenic mice, challenge resulted only in production of
mouse PrPSc, which suggests that human PrP is less
susceptible than mouse PrP to conversion to PrPSc. Incubation
periods to BSE in transgenic mice are unaffected by
expression of human PrP.
Results suggest that these mice lack a species barrier
to human prions and that they can be used to study the
prevention of prion transmission to humans.
ACCESSION NO: 95-96-2252
TITLE: A Short History of Prions
AUTHOR: HOPE, JAMES
JOURNAL: Nature
CITATION: December 21/28, 1995, 378(6559): 761.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: NEURODEGENERATIVE DISEASES; CREUTZFELD-1 JAKOB DISEASE (CJD);
BOVINE SPONGIFORM ENCEPHALITIS (BSE); SCRAPIE; PRIONS;
INFECTIOUS PROTEIN UNITS; VIRUS-LIKE PARTICLES; AMINO-ACIDS;
GLYCOPROTEINS; PROTEINACEOUS INFECTIOUS PARTICLE
ABSTRACT: Creutzfeld-Jakob disease, bovine spongiform
encephalitis, and scrapie are neurodegenerative diseases that
affect humans, cattle, and sheep, respectively. They are
transmitted by feeding or by inoculation and have incubation
periods of from a few months to several years, depending on
dose, route of inoculation, inoculum strain, and the genetics
of the infected species.
In the 1950s experiments showed that the infectivity of
scrapie could pass through filters with pores small enough to
filter out everything but viruses. The infectious agent had
some properties of viruses, such as strain variation, but
differed in being resistant to inactivating processes like
boiling, exposure to ionizing, and ultraviolet radiation,
which kill viruses. In 1967 it was hypothesized these new
infectious particles might not require a nucleic-acid
template, as viruses do. In the scrapie phenotypes, a protein
was the sole particle or an integral part of it. In 1982
researchers found a protein that fitted the hypothesized
molecule and named it the prion protein (PrP). The infectious
particle was designated a prion, from "proin," the acronym
for proteinaceous infectious particle.
In the prion model, the agent is a modified form of the
host-encoded glycoprotein (PrPC). The conversion of PrPC to
PrPSc is thought to occur either by direct interaction of
PrPC with PrPSc, which is the infectious agent. In
spontaneously arising or genetically transmitted disease (CJD
or natural scrapie), it is believed to occur by a rare event
that sparks the self-replicating, catalytic conversion of
PrPC to PrpSc. This conversion has been replicated in in
vitro tests, although it has not yet been demonstrated that
this biochemical change is equivalent to synthesis of
infectious particles.
Many of the physiochemical and epidemiological features
of neurodegenerative diseases can be explained by this model.
However, the mechanism by which different strains of agent
have different effects in the same strain of mouse (which has
a single PrPC amino-acid sequence) is harder to understand.
Some researchers maintain that a second molecule, not PrPC,
determines the strain of infectious particle.
ACCESSION NO: 95-96-1365
TITLE: It Takes Two to Tangle 'Mad Cow' Protein
AUTHOR: COHEN, PHILIP
JOURNAL: New Scientist
CITATION: October 14, 1995, 148(1999): 16-17.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: PRP; PROTEINS; PRIONS; BRAIN; MAD COW DISEASE; SCRAPIE;
CREUTZFELDT-JAKOB DISEASE
ABSTRACT: Researchers believe that the protein behind a group of
fatal brain diseases is transformed into a killer by an
unidentified partner. This partner allows the protein, called
PrP, to change into a disease-causing protein. This protein,
called a prion causes disorders such as "mad cow" disease in
cattle, scrapie in sheep, and Creutzfeldt-Jakob disease (CJD)
in humans.
Researchers, after more than a decade, have produced a
theory of how prions from a diseased brain could replicate.
The prion PrP coaxes normal PrP, found in every mammalian
brain, into assuming the shape of the prion. By remaking
cellular PrP in its image, the prion replicates itself. This
in turn forms deposits that kill the cell, since the prion
form is insoluble.
Experimentation to prove this theory has not been done,
as natural prions may be contaminated with other infectious
agents from diseased brains. In addition, replication of
prions in test tubes has produced too little material for the
experiment.
Currently researchers are using human prions to infect a
special strain of laboratory mice carrying the human PrP
gene. But they had to remove the mouse PrP gene before the
mice could become susceptible to the human prions. It is
believed there is a "X" protein, which accelerates the
activity of PrPs, and only when the mouse PrP is gone will X
react to the human PrP. The researchers must find "X" to
produce infective PrP.
ACCESSION NO: 95-96-1353
TITLE: Another Round in the Prion Debate
JOURNAL: Science News
CITATION: June 17, 1995, 147(24): 383.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: NEURODEGENERATIVE DISEASES; PRIONS; VIRUSES; PROTEINS;
INFECTIONS
ABSTRACT: Researchers looking for the infectious agent that causes
illnesses such as Creutzfeldt-Jakob disease in the human
brain and similar disorders in animals question whether the
agent is a virus or protein. Previously researchers assumed
that these neurodegenerative afflictions resulted for
viruses, but all attempts to isolate and identify viruses
from infectious tissue proved fruitless.
The in 1982, Stanley Prusiner of the University of
California, San Francisco, suggested that the infectious
agent was a type of protein, which he called a prion. He
identified a protein that could act as the hypothetical
prion, and his theory won a strong following.
Other scientists argued that prions cannot produce
infections. Now, an analysis of brain tissue ravaged by
Creutzfeldt-Jakob disease adds weight to that argument. A
research group from Yale University School of Medicine
separated diseased brain tissue and found that the separated
fractions that contained most of the suspected prion proteins
were not significantly infectious. Fractions with proteins
bound to nucleic acids, either DNA or RNA, remained highly
infectious. That suggested the presence of a virus.
To try to rid the infectious fractions of any prions
that might remain, the Yale team treated the samples with a
chemical that breaks down proteins not bound to nucleic
acids. The fractions stayed just as infectious.
ACCESSION NO: 94-95-2014
TITLE: The Prion Diseases
AUTHOR: PRUSIMER, STANLEY B.
JOURNAL: Scientific American
CITATION: January, 1995, 272: 48-57.
YEAR: 1995
PUB TYPE: Article
IDENTIFIERS: PRIONS; NEURODEGENERATIVE DISEASES; SPONGIFORM
ENCEPHALOPATHIES; ALZHEIMER'S DISEASE; SCRAPIE; PROTEIN
SHAPE/PRIONS; INFECTIOUS AGENTS; HUMAN PRION DISEASES
ABSTRACT: Fifteen years ago, scientists were skeptical when it was
proposed that the infectious agents causing certain
degenerative disorders of the central nervous system in
animals and--more rarely--in humans consist exclusively of
protein. They were similarly dubious later, when the same
scientists suggested that these "proteinaceous infectious
particles"--or "prions"--could underlie inherited as well as
communicable diseases. Resistance was met again when they
concluded that prions multiply by converting normal protein
molecules into dangerous ones simply by inducing the benign
molecules to change their shapes. Yet, today, experimental
and clinical data make a convincing case that all three of
the hypotheses are correct.
The known prion diseases, all fatal, are sometimes
referred to as spongiform encephalopathies because they
frequently cause the brain to become riddled with holes. The
most common ailment is scrapie, found in sheep and goats;
another, bovine spongiform encephalopathy (BSE)--or mad cow
disease--is the most worrisome. Human prion diseases are more
obscure: kuru, among highlanders of Papua New Guinea:
Creutzfeldt-Jakob disease, which occurs worldwide in about
one person in a million, typically around age 60 and usually
becomes evident as dementia; Gerstmann-Straussler-Scheinker
disease, usually manifests as ataxia or other damage to the
cerebellum; and fatal familial insomnia, in which dementia
follows difficulty in sleeping.
All of the known prion diseases in humans have now been
modeled in mice. Recent work has inadvertently developed an
animal model for sporadic prion disease. Mice inoculated with
brain extracts from scrapie-infected animals and from humans
afflicted with Creutzfeldt-Jakob disease have long provided a
model for the infectious forms of prion diseases. And the
inherited prion diseases have been modeled in transgenic mice
carrying mutant prion protein (PrP) genes. These models of
human prion afflictions should not only extend understanding
of how prions cause brain degeneration, they should also
create opportunities to evaluate therapies.
Ongoing research may help determine whether prions
consisting of various proteins may play a part in more common
neurodegenerative conditions such as Alzheimer's disease and
Parkinson's disease. There are marked similarities in these
disorders: as is true of the known prion diseases, the more
widespread ills mostly occur sporadically but sometimes "run"
in families; all are usually diseases of middle to later life
and are marked by similar pathology; and in none of these
disorders do white blood cells infiltrate the brain. If a
virus were involved in these illnesses, white cells would be
expected to appear.
Research suggests that the prion is an entirely new
class of infectious pathogen and that prion diseases result
from aberrations of protein conformation. Whether changes in
protein shape are responsible for neurodegenerative diseases
such as Alzheimer's remains unknown, but it is a possibility
that should not be ignored.
ACCESSION NO: 94-95-1128
TITLE: Prying Into Prions
AUTHOR: PENNISI, ELIZABETH
JOURNAL: Science News
CITATION: September 24, 1994, 146(13): 202-203.
YEAR: 1994
PUB TYPE: Article
IDENTIFIERS: NEUROBIOLOGY; PRION DISEASES; AMINO ACIDS; CREUTZFELD-JAKOB
DISEASE; SCRAPIE; SPONGIFORM ENCEPHALOPATHY; PRION PROTEIN
(PrP)
ABSTRACT: In 1982 a researcher at the University of California
proposed that scrapie and some other types of brain diseases
are caused by an infectious protein (prion). In humans the
most common prion disorder is Creutzfeld-Jakob disease, a
spongiform encephalopathy which sometimes runs in families
and is prevalent in Sephardic Jews and families in Chile and
Slovakia. Other diseases, such as Gerstmann-Straussler-
Scheinker syndrome and fatal familial insomnia, occur less
frequently. Only nine families in the world are known to
suffer from the sleep disorder. In prion disease, symptoms
appear suddenly in affected families and affect succeeding
generations. Prions also invade new hosts and can jump
species.
Most pathogens replicate and infect their hosts through
instructions in nucleic acids such as RNA or DNA, but after
years of research, no genes have been associated with
infectious prion particles. It appears that a prion is just a
protein, a string of amino acids, which on its own
accomplishes feats similar to those performed by a much more
complicated molecule. Prion protein (PrP) is normally
anchored to the surface of nerve cells. Scrapie PrP is
chemically the same as PrP from uninfected animals, yet
normal PrP dissolves into water and is destroyed by enzymes
called proteases, while scrapie PrP is insoluble and resists
protease breakdown. The basis of this radical difference lies
in the three-dimensional conformation of the amino acids of
the two forms. Researchers found that by mixing the two forms
in a test tube, they could convert the normal form to the
abnormal form. This means that in a single move, a prion
could both infect a new cell and replicate itself by
transforming the cell's normal PrP to the abnormal form.
Since the abnormal form resists enzyme degradation, the
number of abnormal PrPs accumulate and snowball, These
experimental results now need to be demonstrated in human
tissues.
About 10% of prion diseases have genetic basis, that is,
the gene for PrP mutates. This alteration leads to additions,
substitutions, or deletions among the 253 PrP amino acids.
Depending on the makeup of the rest of the gene, different
diseases can result. A gene sometimes has slight differences
(polymorphisms) in its neucleotide sequences, which affect
the amino acid in the resulting protein. Disease then is
caused by the combination of mutation and polymorphism.
It is not known exactly how PrP leads to disease. Some
researchers assume that accumulations of toxic forms of PrP
lead to the observed destruction. There is also evidence that
imbalances in normal PrP concentrations can harm cells. One
theory suggests that known prion diseases develop after the
accumulation of abnormal protein. As with the development of
amyloid plaques in Alzheimer's disease, researchers theorize
that nerve cells may not like the new shape of the abnormal
PrPs. This may lead to a decrease in numbers of synapses and
the death of nerve cells. In Alzheimer's this process takes
decades, in prion disease it takes years.
British neurobiolgists recently discovered an increased
electrical excitability in brain cells from a mouse strain
created without any gene for PrP. This observation is very
similar to that in humans with Creutzfeld-Jakob disease, who
experience involuntary jerking and seizures. It appears that
PrP must exist in very specific amounts in the body. Mice
producing excess PrP develop muscle disease, and humans with
inclusion body myopathy, a muscular disorder, build up excess
PrP in their muscles. Other similar types of problem may
remain to be discovered.
ACCESSION NO: 94-95-1054
TITLE: Doctors Fail to Recognize Fatal Brain Disease
AUTHOR: BROWN, PHYLLIDA
JOURNAL: New Scientist
CITATION: July 30, 1994, 143(1936)
YEAR: 1994
PUB TYPE: Article
IDENTIFIERS: CREUTZFELDT-JAKOB DISEASE (CJD); RUNWELL HOSPITAL; BRAIN
DISEASES; MAD COW DISEASE; PRIONS; SPONGIFORM
ENCEPHALOPATHIES
ABSTRACT: The number of reported cases of Creutzfeldt-Jakob
disease (CJD), which is a fatal human brain disorder similar
to "mad cow" disease, is believed to be highly underestimated
according to a group of British researchers. This belief is
based on a study of more than 1,000 people who died of
dementia, and is expected to renew public concern about the
way the government is monitoring the disease in the wake of
BSE (bovine spongiform encephalopathy) in cattle.
CJD is one of a group of spongiform encephalopathies
linked to a protein called a prion, which is abnormal in the
brains of sufferers. A few cases of the disease have been
found to run in families that carry a defective gene for the
prion. Others occur merely by chance, and some have even been
blamed on medical treatments where patients received brain
tissues from an infected donor who was improperly screened.
The disease can take decades to incubate, but once symptoms
begin to appear, sufferers rapidly lose their mental
abilities, their sight and control of their limbs. Most die
within 6 mo.
CJD typically affects one in every one million people a
year. However, the group of researchers at Runwell hospital
in Essex, England, are challenging this traditional estimate.
Of the 1,000 people studied who had died of dementia over 25
yr., 19 were shown by laboratory studies to have died of CJD.
Their brains had the characteristic spongy appearance of the
disease and an excess of the abnormal prion protein. But
according to the patients' notes, only 11 of them had been
previously diagnosed as having CJD. The other eight had been
initially, and incorrectly, diagnosed as having other
diseases.
These results raise the concern that many cases of CJD
are actually being mistaken for other types of dementia
because too few postmortem examinations are done. The
researchers are calling for more postmortem examinations to
be done as well as testing to determine the presence of the
abnormal prion protein in order to more accurately determine
the true incidence of the disease. These early studies show
that the epidemiology of CJD is probably far more severe than
was previously thought.
ACCESSION NO: 94-95-0818
TITLE: The Riddle of [URE3]
AUTHOR: BEARDSLEY, TIM
JOURNAL: Scientific American
CITATION: August, 1994, 271: 19-20.
YEAR: 1994
PUB TYPE: Article
IDENTIFIERS: PROTEIN-BASED INHERITANCE; GENETIC INFORMATION;
UREIDOSUCCINATE (URE3); PRIONS; CENTRAL NERVOUS SYSTEM
DISORDERS
ABSTRACT: For several decades, researchers have been intrigued by
a family of fatal central nervous system disorders of humans
and other mammals in which the brain degenerates. These
diseases are notable for the fact that they are not caused by
ordinary infectious agents such as bacteria or viruses, whose
genetic material consists of DNA or RNA. Research strongly
suggests that the agent, called a prion, consists of an
aberrant form of a normal protein and includes no genetic
material. When transmitted from another animal or produced
spontaneously because of a prior mutation, it triggers the
normal form to switch to the prion structure, thus initiating
a runaway process that kills affected cells.
Prions have been considered an isolated curiosity, but
evidence has been found that they have an analogue in yeast.
This evidence derives from research on a metabolic
peculiarity that some mutations confer on yeast cells: the
ability to feed on a chemical called ureidosuccinate. Most
mutations that confer this ability have patterns of
inheritance typical of mutations in genes on chromosomes. But
one--[URE3]--is passed between individuals in ways that
cannot be explained based on what is known about how genes
work. [URE3] is passed on to more offspring than a normal
mutation should be when cells are crossed. It can be
transmitted when cells exchange cytoplasm but not
chromosomes. And a simple chemical treatment can reversibly
"cure" [URE3], thus eliminating the cells' ability to use
ureidosuccinate.
Research has shown that [URE3] can exist in a cell only
if a protein called Ure2p, the product of a known gene, is
present. If a cross is produced that lacks Ure2p, the [URE3]
trait cannot appear in the cell. And a cell that lacks Ure2p
has the ability to metabolize ureidosuccinate.
An explanation of this set of facts is that [URE3] is
not really a mutation at all but rather the manifestation of
cells that contain a variant form of the Ure2p protein. Some
researchers note that there is no experimentation to prove
that the [URE3] trait is transmitted by a protein; still,
there is sufficient interest in the possibility to initiate
various associated studies. One researcher already suspects
that a second genetic system in yeast, [PSI], may follow the
same pattern.
These developments in the prion story are unlikely to
dethrone DNA and RNA as life's principal bearers of genetic
information, but the apparent occurrence of protein-based
inheritance in yeast raises the question of whether such
mechanisms play a bigger role in life and death than has
generally been believed.
ACCESSION NO: 93-94-1128
TITLE: Inheritance Plays Key Role in Brain Disease
AUTHOR: MUNDELL, IAN
JOURNAL: New Scientist
CITATION: October 2, 1993, 140(1893): 10.
YEAR: 1993
PUB TYPE: Article
IDENTIFIERS: GENETICS; CREUTZFELDT-JAKOB DISEASE; BOVINE SPONGIFORM
ENCEPHALOPATHY; DURA MATER TRANSPLANTS; PRION PROTEIN;
HORMONE INJECTIONS
ABSTRACT: Many people who developed Creutzfeldt-Jakob disease
(CJD) after receiving grafts of brain tissue had an in-built
susceptibility to the disorder, according to a leading
American researcher. Lev Goldfarb of the U.S. National
Institutes of Health said at a September meeting of the Royal
Society that the majority of these people had a genetic trait
that predisposed them to the disease.The trait is also
present in most people who develop Creutzfeldt-Jakob disease
spontaneously. Researchers now say it is highly likely that
their disease is triggered by a fault in the brain rather
than an infection.
CJD is a rare, fatal form of dementia related to bovine
spongiform encephalopathy (BSE) or mad cow disease. In
Britain there are about 50 new cases/yr. In a small number of
families CJD is inherited but, until recent years, most cased
developed for unclear reasons.
The BSE epidemic raised fears that some sort of
infectious agent is at work in diseases such as BSE and CJD.
And these worries have been fueled by cases of people who
have contracted CJD after medical treatments. Some received
injections of pituitary hormones taken from the bodies of
people who had suffered from CJD, to treat growth and
fertility problems. In September, the Department of Health in
London announced that others had developed the disease after
receiving grafts of a brain membrane, called dura mater,
during brain surgery. Some of this material also came from
people with CJD.
Goldfarb reported that one particular genetic trait--an
abnormality in the gene that codes for a substance called
prion protein--was present in 86% of those who caught CJD
from dura mater transplants, a significantly higher
proportion than in the general population.
According to Robert Will, head of the National CJD
Surveillance Unit in Edinburgh, Scotland, the majority of
people who develop the sporadic disease have the same genetic
trait as the dura mater cases. He says that this suggests
that the sporadic CJD is likely to be a genetic, rather than
an environmental effect.
A large proportion of people who developed CJD after
receiving hormone injections, with the contaminated material
entering the body through the bloodstream, have a different
abnormality in the prion gene. Will says it appears that the
two genetic traits predispose people to CJD in two different
ways.
There is now considerable evidence that defective prion
protein, not a living organism as some have suggested, is the
"infectious agent" in CJD and BSE. Nobody knows what the
usual role of prion protein is, but normally it is produced
and broken down in a short space of time. Mutation of the
prion gene can, however, produce a form of the protein which
is hard for brain cells to break down. This abnormally-shaped
protein begins to accumulate and "encourages" normal prion
protein to change to its shape by acting as a template. As
protein levels increase, cells begin to malfunction and the
symptoms of the disease appear.
ACCESSION NO: 92-93-2399
TITLE: French Officials Panic Over Rare Brain Disease Outbreak
AUTHOR: ALDHOUS, PETER
JOURNAL: Science
CITATION: December 4, 1992, 258(5088): 1571-1572.
YEAR: 1992
PUB TYPE: Article
IDENTIFIERS: NEUROLOGY; CREUTZFELDT-JAKOB DISEASE; PRIONS; HUMAN GROWTH
HORMONE (HGH); PITUITARY GLAND; CONGENITAL DWARFISM/HGH;
DISEASE TRANSMISSION; ENDOCRINOLOGY
ABSTRACT: In late October, three senior physicians were convicted
by a Paris court for failing to prevent the distribution of
HIV- (human immunodeficiency virus-) infected blood clotting
factors to hemophiliacs. Now, in another public health
scandal, patients treated in the mid-1980s have contracted an
incurable disease after receiving medication derived from
human tissues.
The disease is a rare neurodegenerative condition called
Creutzfeldt-Jakob Disease (CJD)--one of a class of diseases
that are thought to be caused by mysterious infectious agents
called "prions," an altered form of a naturally occurring
protein. The patients were children suffering from congenital
dwarfism, and the source of their infection is believed to be
human growth hormone extracted from the pituitary glands of
cadavers. Eighteen probable cases of CJD in growth hormone
recipients have so far been identified--roughly equal to the
number believed to have been infected through growth hormone
therapy in all other countries combined. Of the 18, nine have
died.
The inspector-general for social affairs has already
launched an investigation that is believed to be focusing on
whether France was unduly slow in switching from natural
growth hormone to the recombinant version, which became
available in the mid-1980s, and whether adequate precautions
were taken to purify the natural product.
In July the French government's health ministry imposed
restrictions on the use of recombinant human growth hormone,
even though it could not possibly contain the CJD agent. The
inspector general's report is due sometime in December, but
in the meantime, researchers are trying to reverse the
decision to restrict the use of recombinant growth hormone.
Epidemiologists are now focusing on a period between
January 1984 and May 1985, during which all of the 18 French
CJD victims identified so far were receiving growth hormone
therapy. Most of the victims are children in their teens or
younger, whereas growth hormone recipients in other countries
who have been struck down with CJD mostly developed symptoms
in their 20s or later.
Researchers suspect that the contaminated hormone
preparations used in France presumably contained a higher
amount of the CJD agent than contaminated batches elsewhere.
One hypothesis to explain this is that one or two extremely
heavily contaminated pituitary glands were somehow included
in a batch from which growth hormone was extracted.
ACCESSION NO: 90-91-1318
TITLE: Slow-Virus Diseases: Mad Cows and Englishmen
AUTHOR: REEVE, MARY PAT
JOURNAL: Harvard Health Letter
CITATION: November, 1990, 16: 1-3.
YEAR: 1990
PUB TYPE: Article
IDENTIFIERS: MAD-COW DISEASE; SCRAPIE; ANIMAL DISEASES; BRAIN
DISORDERS/ANIMALS; PRIONS; FEED PROCESSING; BEEF EXPORTS;
DISEASE TRANSMISSION; INFECTIOUS DISEASE/ANIMALS
ABSTRACT: "Mad-cow" disease, first officially noted in 1986, is
reaching epidemic proportions in Great Britain. The disease
is crippling British cattle production and is currently
forcing the slaughter of 250 to 300 animals a week. The
malady has not been reported outside Britain, but some
European countries and the U.S. have banned the importation
of British beef.
Cattle with the disease may appear quite normal for
several years. They then begin to stagger about, and
previously placid animals can become aggressive and
dangerous. At autopsy, the cow's brain looks spongy and full
of tiny holes under the microscope. Also typical of the
disease are hairlike protein deposits, or fibrils, that build
up in the tissue of the central nervous system.
These features place mad-cow disease with a group of
brain disorders that affect animals and, rarely, humans. The
causal agents in most of these afflictions appear to be
infections, but no one really knows. The protein fibrils seem
to play a crucial role in the disease, but analysis shows
that they are only a modified version of normal host protein.
Because these various diseases appear to be infections and
because the abnormal protein is so far the only laboratory
finding, the causal agent has been dubbed a proteinaceous
infectious particle, or prion. The implication is that these
proteins are causing the infections, but there is no
precedent for an infectious agent totally devoid of genetic
material, either DNA or RNA.
The mad-cow epidemic probably started as scrapie, a
related disease in sheep. In some British feeds, sheep
carcasses are rendered, and the remaining meat protein and
bone meal are added to fodder. Some sheep in the British
Isles have carried scrapie for hundreds of years, and an
occasional carcass presumably contains the infectious agent.
Protein and bonemeal from rendered carcasses has also been
added to feeds for poultry, pigs, and pets, but it is
currently unclear whether these other species will be
affected. There are reassuring indications that, at least for
people, the risk is quite low. People worldwide have been
eating meat from scrapie-infected sheep for hundreds of
years, yet there is no correlation between the prevalence of
scrapie in sheep and for example, Creutzfeldt-Jakob disease
in humans.
In 1989 the report of an expert committee in Britain
concurred that the likely explanation for the bovine epidemic
was a change in feed processing, and stated that cattle are
likely to be "dead-end hosts." The committee also estimated
that the risk of transmission to humans is remote indeed. The
Ministry of Agriculture, Fisheries, and Food has banned the
sale of high-risk tissues (mainly brains and sweetbreads) for
human consumption, and has prohibited the sale of any meat
from animals known to be infected.
The likelihood of an outbreak in U.S. cattle seems small
for several reasons: meat and bonemeal imported from Britain
between 1980 and 1988 were used mainly in poultry feeds, and
birds haven't yet developed the disease; scrapie is not
common in the U.S.; and few rendered animal products are
employed as protein supplements in cattle feed. Nevertheless,
surveillance of cattle in the U.S. has been increased.
ACCESSION NO: 89-90-2053
TITLE: Prions and the Nerve-Muscle Junction
AUTHOR: MILLER, JULIE ANN
JOURNAL: BioScience
CITATION: February, 1990, 40: 88.
YEAR: 1990
PUB TYPE: Article
IDENTIFIERS: PRIONS; DEGENERATIVE NEUROLOGICAL DISEASE; ACETYLCHOLINE
RECEPTOR (AR); AR-INDUCING ACTIVITY (ARIA); MOLECULAR
BIOLOGY; AMINO ACID SEQUENCES; NERVE-MUSCLE JUNCTION
ABSTRACT: A surprising coincidence of amino acid sequence has
opened new speculation about proteins, called prions, that
had already been implicated in several degenerative
neurological diseases. Gerald D. Fischbach and his colleagues
at Washington University School of Medicine in St. Louis have
been studying a protein (called ARIA, for acetylcholine
receptor-inducing activity) from chicken brain that appears
to stimulate the production of acetcholine receptors at
chicken neuromuscular junctions. During development, this
protein may be a signal from nerve cells to muscle, resulting
in the appropriate location of these receptors.
The scientists used molecular biology techniques--
polymerase chain reaction and gene cloning--to determine the
sequence of the ARIA gene from the embryonic chick brain.
When they checked the amino acid sequence of the protein
against other sequences stored in a database, they learned
that ARIA has stretches similar to that of prions, which have
been isolated from other species. It is possible, therefore,
that prions are similar in function to ARIA. Perhaps in
diseases, the appropriate production of receptor molecules is
disrupted causing a loss of nerve-muscle communication and,
eventually, cell death.